Life science
Drug development

Elucidation of mechanism of autoimmune diseases anddrug development targeting neo-self
Laboratory of Immunochemistry, Immunology Frontier Research Center
Professor Hisashi Arase

https://researchmap.jp/read0187233

Department of Immunochemistry, Research Institute for Microbial Diseases
Assistant Professor Hui Jin

https://researchmap.jp/huijinLife science

Abstract
We have prevously shown that HLA class II molecules, which
generally present peptide antigens to T cells, function like a molecular chaperone that transports intracellular unfolded proteins outside the cells. Furthermore, the complex of self-antigen and HLAclass II molecules, neoself, is a target of autoantibodies produced
in a variety of autoimmune diseases. In this study, we analyzed thefunction of neoself and found that the neoself abrogates self-tolerance and triggers autoimmune responses, indicating that the neoself is one of responsible molecules for autoimmune diseases.

of a new type of therapeutic drug that targets neo-self to repair thecause of autoimmune diseases.

▍ Background & Results
Immunity is a defense system against pathogens such as viruses, but autoimmune diseases develop when an immune response
is triggered against self tissues and organs. The host gene thatmost strongly influences the development of autoimmune diseases
is HLA class II, but how HLA class II is involved in disease development has remained unclear. We have shown that HLA class II
molecules function like molecular chaperones, transporting unfolded intracellular proteins outside the cell. Furthermore, molecules
bound to HLA class II molecules have been shown to be antigenically distinct from normal molecules and are the targets of autoantibodies produced in various autoimmune diseases as neo-self.
In this study, we analyzed the pathogenicity of neo-self formed by
HLA class II molecules, which are mainly expressed on specific immune cells and most cells in the body do not express HLA class II.
In Graves’ disease, an autoimmune disease against thyroid tissue,
strong ectopic expression of HLA class II molecules was observedin the thyroid gland, and in addition, a neo-self complex composedof thyroid-stimulating hormone receptors (TSHR) and HLA class
II molecules was detected. Furthermore, neo-self formed by HLA(MHC) class II molecules was found to be a pathogenic moleculethat disrupts autoimmune tolerance and induces the production ofautoantibodies. In summary, the present study demonstrates thatthe formation of neo-self is involved in the pathogenesis of autoimmune diseases. Therefore, elucidation of the mechanism of neoself formation and inhibition of neo-self formation are importantfor elucidating the causes of autoimmune diseases as well as fordeveloping therapeutic drugs.

▍ Significance of the research and Future perspective
This study reveals for the first time that neo-self, a self-antigen/
HLA class II complex, has pathogenic properties that disrupt
self-tolerance and induce autoimmune reactions. Therefore, it is important to understand how neoselves are formed in order to understand the pathogenesis of autoimmune diseases. Current drugs forautoimmune diseases are all symptomatic drugs and require longterm administration. Elucidation of the mechanism of neo-self formation through this study is expected to lead to the development

P a t e n t Japanese Patent No.6373842B2Jin, Hui et al. Abrogation of self-tolerance by misfolded self-antigens complexed with MHC class II molecules. Science Advances. 2022, 8(9): eabj9867.
Tr e a t i s edoi: 10.1126/sciadv.abj9867
UR
L http://immchem.biken.osaka-u.ac.jp
K e y w o r d autoimmune diseases, neo-self, HLA